title: Association between hypermethylation of DNA repetitive elements in white blood cell DNA and early-onset colorectal cancer.
abstract: Changes in the methylation levels of DNA from white blood cells (WBCs) are putatively associated with an elevated risk for several cancers. The aim of this study was to investigate the association between colorectal cancer (CRC) and the methylation status of three DNA repetitive elements in DNA from peripheral blood. WBC DNA from 539 CRC cases diagnosed before 60 years of age and 242 sex and age frequency-matched healthy controls from the Australasian Colorectal Cancer Family Registry were assessed for methylation across DNA repetitive elements Alu, LINE-1 and Sat2 using MethyLight. The percentage of methylated reference (PMR) of cases and controls was calculated for each marker. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using multivariable logistic regression adjusted for potential confounders. CRC cases demonstrated a significantly higher median PMR for LINE-1 (p < 0.001), Sat2 (p < 0.001) and Alu repeats (p = 0.02) when compared with controls. For each of the DNA repetitive elements, individuals with PMR values in the highest quartile were significantly more likely to have CRC compared with those in the lowest quartile (LINE-1 OR = 2.34, 95%CI = 1.48-3.70; p < 0.001, Alu OR = 1.83, 95%CI = 1.17-2.86; p = 0.01, Sat2 OR = 1.72, 95%CI = 1.10-2.71; p = 0.02). When comparing the OR for the PMR of each marker across subgroups of CRC, only the Alu marker showed a significant difference in the 5-fluoruracil treated and nodal involvement subgroups (both p = 0.002). This association between increasing methylation levels of three DNA repetitive elements in WBC DNA and early-onset CRC is novel and may represent a potential epigenetic biomarker for early CRC detection.
authors.affiliation: Cancer and Population Studies Group; Queensland Institute of Medical Research; Herston, QLD Australia.
authors.forename: Rhiannon J
authors.initials: RJ
authors.lastname: Walters
authors.forename: Elizabeth J
authors.initials: EJ
authors.lastname: Williamson
authors.forename: Dallas R
authors.initials: DR
authors.lastname: English
authors.forename: Joanne P
authors.initials: JP
authors.lastname: Young
authors.forename: Christophe
authors.initials: C
authors.lastname: Rosty
authors.forename: Mark
authors.initials: M
authors.lastname: Clendenning
authors.forename: Michael D
authors.initials: MD
authors.lastname: Walsh
authors.forename: Susan
authors.initials: S
authors.lastname: Parry
authors.forename: Dennis J
authors.initials: DJ
authors.lastname: Ahnen
authors.forename: John A
authors.initials: JA
authors.lastname: Baron
authors.forename: Aung Ko
authors.initials: AK
authors.lastname: Win
authors.forename: Graham G
authors.initials: GG
authors.lastname: Giles
authors.forename: John L
authors.initials: JL
authors.lastname: Hopper
authors.forename: Mark A
authors.initials: MA
authors.lastname: Jenkins
authors.forename: Daniel D
authors.initials: DD
authors.lastname: Buchanan
mesh_terms: D000328:Adult; D017668:Age of Onset; D016022:Case-Control Studies; D015179:Colorectal Neoplasms / Q000097:blood* / Q000235:genetics*; D019175:DNA Methylation / Q000235:genetics*; D005260:Female; D006801:Humans; D007962:Leukocytes / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D012091:Repetitive Sequences, Nucleic Acid / Q000235:genetics*
keywords: DNA methylation; colorectal cancer; epigenetics; peripheral blood; repetitive sequence